A Novel “Nihon'’Rat Model of a Mendelian Dominantly Inherited Renal Cell Carcinoma

Abstract

A novel rat model of hereditary renal cell carcinoma (RC) was found in a rat colony of the SpragueDawley strain in Japan, and named the "Nihon" rat. In this strain, RCs develop from early preneoplastic lesions, which begin to appear at 4 weeks of age, forming adenomas by the age of 16 weeks. The RCs are predominantly of clear cell type. Southern blot, northern blot and SSCP analyses revealed no change in the Tsc1, Tsc2, VHL, and c-Met genes. Thus, the Nihon rat should be a valuable experimental model for understanding renal carcinogenesis, especially clear cell type, which is common among human RCs.Key words: Nihon rats -Tsc2 gene mutant (Eker) rats -Renal carcinogenesis -Hereditary cancer Hereditary cancer was first described in the rat by Eker in 1954.1) The Eker rat model of hereditary renal carcinoma (RC) was the first example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. In 1994, Hino and colleagues identified a germline mutation in the rat homologous to the human tuberous sclerosis gene (TSC2) as the predisposing Eker gene.2-4) Recently, we found a novel hereditary RC model in the Sprague-Dawley rat in Japan. We have named this novel RC model the Nihon rat. In this report, we described the origin, transmission mode, and phenotypic and molecular features of Nihon rats.All animals were housed individually in stainless steel cages with wood chip bedding in a room controlled at a temperature of 23±2°C, humidity of 55±10%, with a 12 h lighting cycle (from 6 a.m. to 6 p.m.). The rats were fed a standard diet (CR-LPF, Oriental Yeast Co., Ltd., Tokyo) and were allowed tap water ad libitum. Animals were killed by exsanguination under pentobarbital sodium anesthesia. After necropsy, tissues were fixed in 10% neutral buffered formalin, processed to paraffin-embedded blocks, and sectioned at 5 µm using standard procedures. Sections were stained with hematoxylin and eosin for microscopical examination. Midsagittal sections of each kidney were also stained with periodic acid-Schiff (PAS), and with alcian blue for acid mucopolysaccharides. Tail and kidney DNAs from the original (parent) female rat were extracted as reported. [4][5][6][7][8][9] We used Southern blot, northern blot and SSCP analyses to search for mutations of the Tsc1, Tsc2, VHL, and c-Met genes. The gene-specific primers for Tsc1, Tsc2, VHL, and c-Met [Accession No. AB012279 (primer for exon 17), AB012280 (primer for exon 18) and AB012281 (primer for exon 19), kindly provided by Dr. Y. Kikuchi] were described previously. [4][5][6][7][8][9] Bilateral, multicentric renal tubule tumors were found in 15 out of 343 rats during 5 toxicity studies during the safety evaluation of 3 unrelated chemicals in our laboratory, although renal tumors were found in both treated and non-treated rats (Table I). The age of the rats ranged from 7 to 16 weeks at termination of the treatment period in each of the studies (Table I). The rats had all obtained from the same supplier (Clea Japan Inc., Shiga). At necropsy, bilatera...

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

“…Our data support the second model and strongly suggest that cellular pathways involving the TSC genes provide an alternate pathway to clear cell renal carcinogenesis. Other studies in humans (35)(36)(37)(38)(39), rodents (40), and dogs (41) have also suggested the existence of pathways leading to clear cell renal carcinogenesis that do not involve mutations in the VHL genes. In contrast to these previous reports, in which the genetic components of the alternate pathways are unknown, all of the patients in our study are known to have TSC.…”

Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein

“…The Eker rat has a germline alteration in the homolog of human TSC2 (Tsc2), a predisposing gene of the tuberous sclerosis complex (Kobayashi et al, 1995). The Nihon rat has been characterized by earlier development and more aggressive phenotypes of RCs relative to the Eker rat (Okimoto et al, 2000). Heterozygous Nihon mutant rats develop RCs that mainly show clear-cell histology.…”

Renal Cell Carcinoma in Humans and Animals: A Brief Literature Review

“…Apparently some animals are genetically predisposed to certain neoplasms. Renal neoplasm is reported to be an inherited genetic disease in various species of rats [35][36][37][38][39][40][41][42][43]. Hereditary renal cystadenocarcinoma is reported in German shepherd dogs [17].…”

“…Various renal tubular tumors including RCC are reported and described as familial in laboratory rat, Long-Evans derived Eker rats and the Nihon rat [35][36][37][38][39][40]. Furthermore, familial renal cell tumors are also suspected in F344 and Sprague-Dawley rats [41][42][43].…”